Glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) are fragments of the proglucagon molecule and the proglucagon molecule has a sequence of 160 amino acids. Proglucagon originates from preproglucagon which is synthesised in the L-cells in the distal ileum, in the pancreas and in the brain. Processing of preproglucagon to give GLP-1 and GLP-2 occurs mainly in the L-cells.
The amino acid sequence of the proglucagon fragment 72-117 is given i.e. by Bell, G. I. et al. (Nature 304 368-371 (1983)). The proglucagon fragment 78-108 is commonly referred to as GLP-1 (7-37). In analogy with this, the proglucagon fragment 72-108 is in the present text also referred to as GLP-1 (1-37).
The proglucagon fragment of GLP-1 (7-36)amide is the naturally occurring form in humans and is usually referred to as GLP-1. Gutniak, M., N Engl. J. Med., 326:1316-22 (1992).
A simple system is used to describe fragments and analogues of the GLP-1 related peptide. Thus, for example, Gly8-GLP-1 (7-37) designates a fragment of GLP-1 formally derived from GLP-1 by replacing the amino acid residue in position 8 (Ala) by Gly.
Variants of GLP-1 (7-37) and analogues thereof have been disclosed, for example, Gln9-GLP-1 (7-37), D-Gln9-GLP-1 (7-37), acetyl-Lys9-GLP-1 (7-37), Thr16-Lys18-GLP-1 (7-37), Lys18-GLP-1 (7-37) and the like, and derivatives thereof including, for example, acid addition salts, carboxylate salts, lower alkyl esters, and amides (see e.g. WO 91/11457).
Glucagon-like peptide-1 (GLP-1) is known to stimulate insulin secretion and inhibit glucagon secretion and thereby lowers blood glucose, Andreasen, J. J. et al. (Digestion 55 221-228 (1994)). Generally, the various disclosed forms of GLP-1 are known to stimulate insulin secretion and cAMP formation (see e.g., Mojsov, S. (Int. J. Peptide Protein Research 40 333-343 (1992))).
Glucagon-like peptide-2 (GLP-2) is a 33 amino acid peptide fragment of proglucagon corresponding to the sequence of the proglucagon fragment 126-158. GLP-2 shows remarkable homology in terms of amino acid sequence to glucagon and glucagon-like peptide-1 (GLP-1). Further, different mammalian forms of GLP-2 are highly conserved. For example, the human GLP-2 (hGLP-2)and the degu (a south American rodent) GLP-2 differ from rat GLP-2 (rGLP-2) by one and three amino acids respectively.
Various vertebrate forms of GLP-2 have been reported by many authors including Buhl et al., J. Biol. Chem., 1988, 263 (18):8621, Nishi and Steiner, Mol. Endocrinol., 1990, 4:1192-8, and Irwin and Wong, Mol. Endocrinol., 1995, 9 (3):267-77. The sequences reported by these authors are incorporated by reference.
When given exogenously, GLP-2 can produce a marked increase in the proliferation of small intestinal epithelium of the test mice, apparently with no undesirable side effects (Drucker et al., 1996, PNAS:USA, 93 7911-7916). Moreover, GLP-2 has also been shown to increase D-glucose maximal transport rate across the intestinal basolateral membrane (Cheeseman and Tseng, 1996, American Journal of Physiology 271 G477-G482).
Osteoporosis is the most common bone disease in humans. It is a serious and frequent disease, which occurs worldwide. The single most important risk factor for osteoporosis is oestrogen deficiency, and it is estimated that up to one third of postmenopausal women will be affected if left untreated, Schlemmer, A. et al., Eur. J. Endocrinol. 140:332-337 (1999). A primary event leading to osteoporotic bone loss is the increase in bone turnover associated with menopause. The acute increase in bone resorption seen with the decline in endogenous oestrogen production is followed by a coupled, but less accentuated increase in bone formation. This net imbalance between resorption and formation results in bone loss thereby increasing fracture risk.
Other diseases and metabolic disorders which result in loss of bone structure are for instance, hyperparathyroidism, Paget's disease, hypercalcemia of malignancy, osteolytic lesions produced by bone metastasis, bone loss due to immobilisation or sex hormone deficiency, Behcet's disease, osteomalacia, hyperostosis and osteopetrosis.
Surprisingly, it has now been discovered that administered GLP-1 peptide or GLP-2 peptide have an effect on loss of bone mass and/or insufficient bone formation in humans. Based on these observations it is now possible to provide a medicament and a method for the prophylaxis or treatment of diseases or disorders wherein bone resorption and/or insufficient bone formation is a factor, such as osteoporosis.